This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our hypothesis is that primary SIVsm isolates belonging to different lineages are not intrinsically as highly virulent in rhesus macaques (Rh) as the reference strains. Rh infection with primary SIVsm isolates may be a better model for HIV-1. Nine different phylogenetic lineages showing similar degrees of divergence as HIV-1 subtypes co-circulate in Primate Centers. Emergence of highly pathogenic SIVmac strains in Rh is related to multiple serial passages. Our specific aims (SA) are: SA1: To assess the in vivo pathogenesis of primary SIVsm strains belonging to lineages 1 (ancestors of B670), lineage 8 (ancestors of SIVmac) and lineage 6 (not previously tested in Rh but highly neutralizable in SMs) and to compare them to the highly pathogenic prototype SIVs (SIVsmB670 and SIVmac251). We will extend the preliminary results obtained during a pilot study to acquire statistically significant data and to confirm that SIVsm infection can indeed be controlled by Rh. We will investigate the immunopathogenesis of SIVsm infection and the immune effectors (cellular and humoral) involved in the control of viral replication in Rh. Viral determinants of pathogenicity will be investigated. SA2: To examine the role of CD8+ T cells in controlling viral replication and disease progression in Rh infected with primary SIVsm isolates. CD8+ T cells play an important role in controlling pathogenic lentiviral infections. We hypothesize that viral replication in Rh infected with primary SIVsm isolates is controlled by CD8+ T cells. Therefore, we will deplete CD8 T cells during acute and chronic SIVsm infection. The outcome of SIVsm infection will be compared between depleted and non-depleted Rh, to determine if differences occur in plasma and tissue VLs, immunologic markers and disease progression. CTL activity during SIVsm infection with these low pathogenic lineages will be investigated on selected time points. The study of these ?ancestral? viruses will offer valuable insights into the discrete mechanisms of control of SIV infection. The diversity of the different SIVsm lineages is similar to that of HIV-1 group M subtypes, therefore by providing a large array of well characterized SIVsm strains mirroring HIV-1 diversity we will provide an useful model for pathogenesis and vaccine studies.